Vascular smooth muscle cells (VSMC) in the blood vessel wall normally exhibit a differentiated, contractile phenotype. However, in response to arterial injury or hypercholesterolemia, VSMC dedifferentiate and proliferate leading to neointima formation-one of the hallmarks of arteriosclerosis. The molecular mechanisms regulating this phenotypic modulation are still not well defined. Understanding the transcriptional control of genes expressed in VSMC will provide insights into the complex regulatory mechanisms of VSMC differentiation, dedifferentiation and proliferation. Cysteine-rich protein (CRP) 2, also known as smooth muscle LIM protein (SmLIM), is a member of the LIM-only CAP family. CRP2 is expressed in arterial, but not venous smooth muscle cells (SMC). CRP2 expression is down regulated in response to arterial wall injury. Thus, we hypothesize that CRP2 may play an important role in the blood vessel wall remodeling under pathological conditions. Understanding the transcriptional regulation and function of CRP2 may provide insight into the phenotypic modulation of arterial SMC. Our goals are to investigate the transcriptional regulation of CRP2 gene expression in arterial SMC and to determine the biological function of CRP2 in vascular remodeling. We propose the following: AIM 1. Investigate the molecular mechanisms regulating CRP2 expression in arterial SMC. In vivo footprinting experiments and transgenic mouse studies will be performed to identity arterial SMC-specific elements. AIM 2. Determine whether an absence of CRP2 protein alters vascular remodeling under pathological conditions. We have generated CRP2 null mice and will subject these mice to models of arteriosclerosis. AIM 3. Determine whether CRP1 acts in conjunction with CAP2 to modulate the phenotype of arterial SMC. We hypothesize that CAP 1, a closely related protein that is expressed in SMC, may also contribute to the vascular remodeling. We will generate CRP1 and CRP2 double null mice and subject the mice to vascular disease models. The proposed experiments will allow us to determine the role of CRP2 in the phenotypic modulation of VSMC in arteriosclerosis. Information obtained from these experiments should provide not only fundamentally important knowledge about the dedifferentiation and proliferation of VSMC but also critical insight into the treatment of arteriosclerosis.